Diabetes is a growing epidemic that is estimated to affect over 300 million people by the year 2025, for which Type 2 diabetes accounts for 90-95% of all cases. Complications resulting from sustained elevated plasma glucose levels include cardiovascular disease, nephropathy, neuropathy, and retinopathy. In addition, the β-cells of the pancreas are destroyed and thus insulin secretion ceases during the later stages of the disease. Current treatments for diabetes can result in hypoglycemia and weight gain, and because patients may become resistant to treatment regimens over time, this may culminate in the need for insulin therapy at later stages of the disease (Narayan et al., Diabetes Research and Clinical Practice 50:S77-S84, 2000; Moller, Nature 414:821-827, 2001).
Glucagon like peptide-1 (GLP-1) is a 30-amino acid peptide (SEQ ID NO: 17) secreted from the L-cells of the intestine following an oral glucose challenge (Mojsov et al., J. Biol. Chem. 261:11880-11884, 1986; Orskov et al., Diabetes 43:535-539, 1994; Drucker et al., Proc. Natl. Acad. Sci. USA 84:3431-3438, 1987; Suzuki et al., Endocrinology 125:3109-3114, 1989). In response to glucose, GLP-1 binds to the GLP-1 receptor (GLP-1R) on the pancreas and induces insulin secretion (human GLP-1R amino acid sequence shown in SEQ ID NO: 1, mouse GLP-1R amino acid sequence shown in SEQ ID NO: 2). It has also been shown that GLP-1 reduces gastric emptying which decreases the bolus of glucose that is released into the circulation and may reduce food intake (Wettergren et al., Dig. Dis. Sci. 38:665-673, 1993). GLP-1 has also been shown to inhibit apoptosis and increase proliferation of the β-cells in the pancreas (Drucker et al., Mol. Endocrinology 17:161-171, 2003; Perfetti et al., Endocrinology 141:4600-4605, 2000; Hui et al., Endocrinology 144:1444-1455, 2003; Farilla et al., Endocrinology 143:4397-4408, 2002). Thus, GLP-1 has attractive properties for a therapeutic to lower blood glucose and preserve the β-cells of the pancreas of diabetic patients.
It is likely that functional GLP-1 receptors localized in different types of tissues and cells contribute to the overall observed efficacy of the pleiotropic GLP-1 peptide. For example, it is unclear whether GLP-1 regulates food intake via a centrally or peripherally-mediated mechanism. Current GLP-1R tissue distribution studies have relied almost entirely upon mRNA levels rather than protein levels (Bullock et al., Endocrinology 137:2968-2978; Valverde et al., Endocrine 23:77-84, 2004). Further receptor biodistribution studies would benefit from the availability of specific GLP-1R antibodies that cross-react across species, thus facilitating measurement of protein levels for example in defined brain regions and peripheral tissues across multiple species. Antibodies that identify and neutralize the activity of the GLP-1R would facilitate phamacodynamic studies. For example, the antibody could be used as a tool to dissect the contributions of brain versus peripheral GLP-1 receptors that may be responsible for mediating GLP-1 effects.
Therefore, there is a need for antibodies against GLP-1R that facilitate biodistribution, pharmacodynamic, and mechanism of action studies of the GLP-1R and its ligands.